The precise balance for the survival and apoptosis is fundamental during development and in adult. Growth factors play critical roles in such balance, and therefore are potential therapeutic agents for effective treatment of a variety of diseases. My laboratory is interested in the cellular and molecular mechanism mediating the diverse functions of glial cell line-derived neurotrophic factor (GDNF). This growth factor was originally discovered as a potent survival factor for midbrain dopaminergic (DA) neurons. It has now been established that GDNF belongs to a family of growth factors (GNFs) that include neurturin (NRTN), artemin, and persephin (PSP), and their functions are mediated by GPI-linked binding proteins, GFRa1-4, and a receptor tyrosine kinase, c-RET. Employing targeted mutagenesis approach, we have uncovered widespread defects in developing and adult Gdnf deficient mice. We are continuing our studies on GNFs, using a combination of molecular, biochemical and electrophysiological approaches. Gdnf-/- mice die at birth due to defects in the kidney and gastrointestinal tract. Although GDNF has been shown to prevent lesion-induced death of midbrain DA neurons, its function in normal brain remains unclear. To address this question directly, we study the role of GDNF on DA neurons in cultures and in adult brain slices using an electrophysiological approach. We discovered an unexpected, acute effect of GDNF on A-type potassium channels, leading to a potentiation of neuronal excitability. Further, we show that GDNF regulates the K+ channels through a mechanism that involves activation of MAP kinase. Thus, this study has revealed, for the first time, an acute modulation of ion channels by GDNF. Our findings suggest that the normal function of GDNF is to regulate neuronal excitability, and consequently dopamine release. These results may also have implications in the treatment of Parkinson's disease (Nature Neuroscience). Another major neuronal population that GDNF supports is the motoneurons in the spinal cord. Motoneuron loss is the hallmark of the devastating disease of Amyotrophic Lateral Sclerosis (ALS). We previously shown that a substantial motoneuron loss in Gdnf-/- spinal cord, and studied the mechanism of GDNF during motoneuron development and survival. Our results demonstrated that GDNF is the first growth factor qualified as a bona fide motoneuron survival factor in vivo (J. Neuroscience). Recently, we study further the role of GDNF during neuromuscular development, a Xenopus nerve-muscle co-culture system was used, in collaboration with Dr. Bai Lu at NICHD, NIH. Long-term application of GDNF significantly increased the total length of neurites in the motoneurons, as well as an increase in number and size of the synaptic vesicle clustering. Electrophysiological analysis revealed two effects of GDNF on synaptic transmission. 1) GDNF markedly increased the frequency of spontaneous transmission and decreased variability of evoked transmission, suggesting an enhancement of transmitter secretion. 2) GDNF elicit a small increase in quantal size, without affecting the average rise and decay times of synaptic currents. Imaging analysis showed that the size of the acetycholine receptor clusters at synapses increased in muscle cells overexpressing GDNF. Neurturin (NRTN), a member of the GDNF family molecular had very similar effects as GDNF. This study suggested GDNF and NRTN are new modulators that regulate the development of the neuromuscular synapse through both pre- and postsynaptic mechanism. Thus, GDNF and its family members are not only important for the survival of motoneurons or other neuronal population in the brain, but also important modulators of synaptic activity in adult (J. Biol. Chem.). Dissecting the genetic susceptibility to complex human diseases is challenging, due to many constraints in human, such as genetic heterogeneity, environmental factors, and sporadic occurrence. These constraints greatly diminish the power of modern human genetics tools to discern potential genetic link between diverse phenotypes (variability of disease severity, presentation, age of onset, etc.) to a single genetic locus. The situation is worsened when genetic alterations lie outside of the coding sequence. To overcome these constraints in human and to develop more effective strategy to enhance the resolution of discerning subtle genetic or epigenetic alterations as a mechanism for human disease susceptibility, a reverse population genetics approach, i.e., a population study in a cohort of mice with defined genetic alteration, was developed. The effectiveness of this approach was demonstrated by linking Gdnf locus to Hirschsprung disease (HSCR) susceptibility in a cohort of mice lacking one functioning Gdnf allele. The mutant cohort recapitulates characteristic features of the human disease. This novel model allows us to study the developmental mechanisms of disease pathogenesis that might be relevant to most HSCR patients. In a broader sense, our results establish a general paradigm for dissecting the genetic basis for human disease susceptibility in mice (Am. J. Human Genet.).